The present invention is directed to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, and in particular for the treatment of pain.
The xcex4 receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the xcex4 receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the xcex4 receptor have also been shown to possess immunomodulatory activities.
The identification of at least three different populations of opioid receptors (xcexc, xcex4 and xcexa) is now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated.
With few exceptions, currently available selective opioid xcex4 ligands are peptidic in nature and are unsuitable for administration by systemic routes. One example of a non-peptidic xcex4-agonist is SNC80 (Bilsky E. J. et al., Journal of Pharmacology and Experimental Therapeutics, 273(1), pp. 359-366 (1995)). There is however still a need for selective xcex4-agonists having not only improved selectivity, but also an improved side-effect profile.
Thus, the problem underlying the present invention was to find new analgesics having improved analgesic effects, but also with an improved side-effect profile over current xcexc agonists, as well as having improved systemic efficacy.
Analgesics that have been identified and are existing in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred xcex4 agonist compounds, described within the prior art, show significant convulsive effects when administered systemically.
We have now found that certain compounds not specifically disclosed by, but included within the scope of WO 97/23466, exhibit surprisingly improved xcex4-agonist properties and in vivo potency.
The novel compounds according to the present invention are defined by the formula I 
wherein
R1 is selected from any one of 
where each R1 heteroaromatic ring may optionally and independently be further substituted by 1, 2 or 3 substituents selected from straight and branched C1-C6 alkyl, NO2, CF3, C1-C6 alkoxy, chloro, fluoro, bromo, and iodo. The substitutions on the heteroaromatic ring may take place in any position on said ring systems;
A preferred embodiment of the present invention is a compound according to FIG. 1 wherein R1 is as defined above and each R1 phenyl ring and R1 heteroaromatic ring may independently be further substituted by a methyl group.
A more preferred embodiment of the present invention is a compound according to FIG. 1 wherein R1 is pyridinyl, thienyl or furanyl.
Within the scope of the invention are also separate enantiomers and salts of the compounds of the formula I, including salts of enantiomers.
Separation of racemic mixtures into separate enantiomers is well known in the art and may be accomplished for example by separation on a suitable chiral chromatography column. Preparation of salts is well known in the art, and may be accomplished for example by mixing a compound of formula I in a suitable solvent with the desired protic acid and isolation by means standard in the art. Salts of compounds of formula I include pharmaceutically acceptable salts and also pharmaceutically unacceptable salts.
When the heteroaromatic ring(s) are substituted, the preferred substituents are selected from anyone of CF3, methyl, iodo, bromo, fluoro and chloro.
Key reaction step Scheme 1, vide infra, is performed by reacting an intermediate compound of the general formula II 
wherein R is an N-protecting group such as Boc or CBz, and P is a O-protecting group such as TBS or Me, which is first N-deprotected and then alkylated using either,
i) a compound of the general formula R1xe2x80x94CH2xe2x80x94X, wherein R1 is as defined above and X is halogen, preferably bromide, and a suitable base, or
ii) a compound of the general formula R1xe2x80x94CHO, wherein R1 is as defined above, and a suitable reducing agent to give the compounds of general formula I, after O-deprotection.
Suitable bases to be used in the standard alkylation step i) above includes, but is not limited to, triethylamine and potassium carbonate.
Suitable reducing agents to be used in the standard reduction step ii) includes, but is not limited to, sodium cyanoborohydride and sodium triacetoxyborohydride.
The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive.
Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents.
Compounds of the invention are useful in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
Compounds of the invention are useful for the treatment of diarrhoea, depression, anxiety, urinary incontinence, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (eg. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.
Also within the scope of the invention is the use of any of the compounds according to the formula I above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.
A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such treatment.
A further aspect of the present invention is intermediates of the general formula II, 
wherein R is an N-protecting group such as Boc or CBz, and P is a O-protecting group such as TBS or Me.
Methods of Preparation
The compounds according to the present invention may be prepared by following any one of the procedures described in Schemes I, II, III and IV below. Similar procedures are described in J. March, Advanced Organic Chemistry, 4th Edition, John Wiley and sons (1992); Katritsky, A. R., Lan, X Chem. Soc. Rev., pp. 363-373 (1994), which are hereby incorporated by reference. 